Rationale: Panic attacks are common in chronic obstructive pulmonary disease (COPD), and the prevalence of panic disorder is at least 10 times higher than in the general population. In the current study, we examined resistive load perception in patients with COPD with and without panic attacks. Objectives: We tested competing hypotheses, based on conflicting results of earlier studies, that those patients with COPD with panic attacks or panic disorder would show either heightened or blunted perception of dyspnea as the magnitude of inspiratory resistive loads increased.

Measurements and Main Results: We administered a diagnostic interview for panic attacks and panic disorder. We measured perceived dyspnea in response to increasing inspiratory resistive loads (modified Borg scale) and several respiratory variables. Dyspnea ratings increased linearly for all groups as the size of resistive loads increased. No significant differences were found between groups on the respiratory variables. Patients with COPD with panic attacks or panic disorder rated their level of dyspnea significantly higher than did other subjects.

Conclusions: Patients with COPD with panic attacks showed heightened sensitivity to inspiratory loads. The result reinforces the influence of psychological factors on symptom perception in this disease.

The influence of psychological variables on symptom perception in respiratory disease is a topic of growing interest to researchers and clinicians. Anxious and depressive symptoms are frequently present in patients with chronic obstructive pulmonary disease (COPD), and predict poorer quality of life and functional status (1- 7). Panic attacks are common in COPD, and the prevalence of panic disorder has been estimated to be at least 10 times higher than the prevalence of 1.5 to 3.5% in the general population (8, 9). Despite the difficulties of diagnosing panic disorder in the context of a respiratory disease, it can be differentiated by recurrent panic attacks, which are unexpected and unpredictable on some occasions, and the presence of anticipatory anxiety about further attacks (10).

Inspiratory resistive load testing is frequently used in dyspnea research, to increase the effort and work of breathing (11-13). Surprisingly, despite extensive use of resistive load testing in physiologic research, and the frequent discrepancy between respiratory patients' self-reported dyspnea and the extent of pathophysiology, few studies have investigated the effects of psychopathology on ratings of perceived dyspnea (14, 15). Two early studies by Hudgel and colleagues (16, 17) found that of 12 subjects with asthma and 12 normal subjects, those with high scores on a "panic-fear scale" had a higher threshold for detecting resistive loads to breathing, whether they were asthmatic or not. Similarly, Tiller and colleagues (18), with a sample of eight subjects (without respiratory disease) diagnosed with panic disorder and eight healthy control subjects, found that patients with panic disorder appeared to be less able than control subjects to estimate the relative size of added inspiratory resistive loads. The results of these two studies suggest that sensitivity to respiratory stimuli may be blunted in anxious individuals. However, there are some limitations to the studies that warrant caution. The sample sizes were small, as were the magnitudes of resistive loads, and the subjects were not asked to rate the level of dyspnea that they were experiencing.

More recently, Lavietes and coworkers (19) reported on 29 subjects with chronic fatigue syndrome (chosen because of an association between this syndrome and somatization) and 23 healthy control subjects who rated their degree of dyspnea in response to small and moderate inspiratory resistive loads. Although no differences in ventilatory parameters were found between subjects, those with higher levels of depression reported higher levels of dyspnea. Meek (20), in a study comparing 30 patients with COPD and 30 healthy control subjects, found that ratings of dyspnea during resistive loading were higher when patients with COPD were asked to focus attention on their clearest memory of dyspnea. Meek concluded that the increase in dyspnea ratings was due to the negative emotions evoked by recalling an episode of dyspnea. Given that subjects in the first three studies cited above did not have COPD, it is uncertain whether the findings would also apply to patients with COPD. However, whether anxious patients with COPD have heightened or blunted perception of dyspnea has not been tested.

In the current study, we investigated inspiratory resistive load perception in patients withCOPDwith and without panic attacks. The existing literature leads to two competing hypotheses. From the early work of Hudgel and colleagues (16, 17) and Tiller and colleagues (18), it would be predicted that the presence of panic attacks or panic disorder in individuals with COPD may be associated with blunted perception of dyspnea in response to increasing inspiratory resistive loads. In contrast, on the basis of Lavietes and colleagues' (19) and Meek's (20) studies, it would be predicted that the presence of panic attacks or panic disorder in patients with COPD may be associated with a heightened perception of dyspnea. Therefore, the aim of our study was to test these two opposing hypotheses. Some of the results of this study have previously been reported as an abstract (21).

METHODS

Subjects and Data Collection

Ninety-six consecutive patients with moderate to severe COPD, from Prince of Wales Hospital, Sydney, Australia, were approached to participate. Data were collected for the 52 (54%) who agreed. Procedures were approved by the local ethics committee, and written, informed consent obtained. Age-matched control subjects with no significant medical illnesses were recruited from the local community. Subjects were tested at 10 A.M. They performed a selective attention task (22) before inspiratory resistive load testing. The Hospital Anxiety Depression Scale (HADS) (23), a well- validated (24) self-report measure of anxious and depressive symptoms, and the Panic Disorder and Agoraphobia sections of the Anxiety Disorders Interview Schedule (ADIS-IV) (25) were then completed. The ADIS-IV is a structured clinical interview that is considered to be the gold standard for the diagnosis of panic attacks and panic disorder, using criteria from the American Psychiatric Association's Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) (10). The experimenter was blind to the HADS and ADIS-IV results at the time of resistive load testing. Twenty (11 female) of the 52 patients with COPD were diagnosed with panic attacks (n = 11) or panic disorder (n = 9) (COPD panic group). Those with panic attacks had been experiencing attacks for a mean 37 +- 24 months, and those with panic disorder had been experiencing attacks for a mean 45 +- 27 months. All had begun to experience panic attacks after the onset of their COPD, and none with panic disorder had been formally diagnosed before the current assessment. Those with panic attacks had experienced a mean 3.4 +- 3.1 attacks in the previous month, whereas those with panic disorder had experienced a mean 4.7 +- 4.3 attacks. From the remaining 32 patients, we selected at random 20 patients (10 female) without panic attacks or disorder (COPD no panic group), age matched to the first group. We compared resistive loading from these two groups with data from 20 age- matched control subjects (11 females) (healthy control group), none of whom had panic attacks or disorder. The mean age of subjects was 72.6 (+-7.0; range, 56-86) years. Those with COPD had received their diagnosis an average 6.8 (+-5.14) years previously, and all had COPD as their primary diagnosis. Patients with COPD with secondary diagnoses were only accepted if any other medical conditions were stable and under good control. None had any other respiratory condition or vocal cord dysfunction, which has been associated with panic disorder in patients with respiratory disease (26). The COPD groups were similar in frequency and types of comorbidities. All subjects with COPD had used their usual morning bronchodilator medications before resistive load testing, so any effects of bronchodilator medication on perception of the loads would apply equally to both groups. Three subjects in the COPD panic group were receiving alprazolam twice a day, and used it on the morning of testing. However, we consider that having had this anxiolytic medication can only have decreased the subjects' anxiety level and any effect of anxiety on dyspnea ratings and respiratory function. The three groups did not differ on demographic variables. Subjects returned another morning within 2 weeks for pulmonary function testing using standard spirometry to measure FEV^sub 1^ and FVC. Those with COPD were asked not to take their usual bronchodilator medication, if possible, before attending the testing session. Resistive Load Testing

The modified Borg scale (27) was used to quantify the perception of respiratory sensation during resistive loading. Wearing a nose clip, subjects breathed through a mouthpiece and two-way valve (Hans Rudolph, Kansas City, MO). Inspiratory flow was integrated to give inspired volume. Inspiratory mouth pressure was measured (Validyne, Northridge, CA). Subjects could be switched from normal breathing to inspire through one of five resistive loads, presented in random order. To allow comparison of the way subjects breathed through the loads, for each loaded breath we measured inspiratory time (TI), inspiratory volume (VT), inspiratory flow (V), and inspiratory pressure (PI). Loads corresponded to 5.4 (load 1), 19.8 (load 2), 35.3 (load 3), 45.0 (load 4), and 126.44 (load 5) cm H2O/L per second. Subjects were told: "I'll be asking you to breathe normally through this mouthpiece. I'll be changing the resistance to breathing, and each time I do, I'll ask you to signal the level of difficulty with your breathing that you are feeling. Signal with this dial. Whenyou turn the dial, the light moves up from 0 to 9.5. Try to use the full range of the scale in deciding on your ratings." Resistive loads were then added during stable ventilation, with three trials of each load (15 trials in all, in addition to practice trials with no load, load 1, and load 4), and at least 30 seconds between loads. After four consecutive stable loaded breaths, the subject rated breathing difficulty, and the load was then immediately removed (Figure 1). Expiration was not loaded. Subjects were free to choose their breathing rate, volume, and flow to have as natural a breathing pattern as possible. Therefore, the resistance was calculated according to the actual flow during the inspiratory phase for each load. The relationship between flowand pressure was linear through each of the loads for the range of inspiratory flows adopted by the subjects.

Statistical Analysis

V and PI were calculated between 25 and 75% of total TI, and correlated closely with peak values and mean values across the breath. For each load, data for three breaths were averaged. For each subject, data from the three applications of each load were averaged. We calculated effective resistance (Reff) for each load by dividing mean PI by mean V. We used a predictive equation for the perceived magnitude of external inspiratory resistive loads (Psi) [Psi = PI^sup (1.5)^ x TI^sup (0.6)^] (28) to calculate a value for Psi for each load for each subject.

SPSS version 12.0 (SPSS, Inc., Chicago, IL) was used for analyses. One-way analyses of variance (ANOVAs) investigated which variables differed between groups. Five by three mixed model analyses of covariance, with mean score for each of the five key respiratory variables (TI, V, PI, Reff, and Psi) and mean Borg ratings as the within-subjects factor, and group as the between- subjects factor, were then performed, controlling for any variable that differed significantly between the groups.

RESULTS

See Table 1 for mean characteristics of the subjects in the age- matched COPD panic, COPD no panic, and healthy control groups. There were no significant differences in body mass index between subjects in the three groups. There were significant differences between the groups on the respiratory function measures of FEV^sub 1^ and FVCbefore bronchodilator medication (medication was not administered to healthy control subjects). Planned comparisons confirmed that, whereas both COPD groups differed significantly from healthy control subjects before medication (P

There was a significant difference between the three groups on the HADS anxiety scale total score. Planned comparisons indicated that this result was due to significant differences between the COPD panic and the COPD no panic (P

For each respiratory variable, a significant main effect for resistive load magnitude was found. For subjects in all three groups, as the magnitude of the loads increased, PI increased significantly from 2.6 to 12.3 cm H2O (P

For mean Borg ratings, there was a highly significant main effect for load magnitude across groups (P

DISCUSSION

On the basis of previous studies (16-20) using the resistive load- testing paradigm to investigate the effects of psychopathology on symptom perception, we had posed two competing hypotheses: That patients with COPD with panic attacks or panic disorder would show either blunted, or heightened, perception of dyspnea as the magnitude of inspiratory resistive loads increased, compared with patients withCOPDwithout panic attacks and healthy control subjects. Our results supported the latter hypothesis. For COPD panic subjects, as for other subjects, a linear increase in perceived dyspnea as resistance increased was observed. However, COPD panic subjects' ratings of level of difficulty with their breathing were consistently significantly higher than those of subjects with COPD without symptoms of anxiety disorder or healthy control subjects. Increased anxiety led to heightened, not blunted, sensitivity to the inspiratory loads.

We found no differences in the spirometric measures of FEV^sub 1^ andFVCbetween patients withCOPDwith panic attacks or panic disorder and those without. Although subjects were free to choose how they breathed through the inspiratory load, we also found no significant differences in V, PI, TI, and the two other calculated respiratory variables, between the COPD panic, COPD no panic, and healthy control groups during resistive load testing. There were significant main effects for changes in breathing on all of these variables as load magnitude increased.However, all subjects seemed to breathe through each of the loads similarly. In a larger sample, some differences in respiratory variables between patients with COPD with panic attacks and those without may have emerged. In this sample, despite the absence of differences in respiratory variables, COPD panic subjects showed heightened symptom perception. Our results are consistent with those of Lavietes and colleagues (19), who also concluded that subjects' experience when breathing with a resistive load cannot be fully accounted for by the ventilatory response to the load. The current results provide support for psychological theories of panic disorder, in particular the cognitive model (29, 30). In this model, the individual's catastrophic interpretations of ambiguous physical sensations (such as dyspnea) increase arousal, creating a positive feedback loop that results in panic. Such sensations may be interpreted as meaning, for example, that the individual may stop breathing, faint, or die. These interpretations increase anxiety further, creating a vicious cycle. The proven existence of biases in panic disorder patients without respiratory disease toward the threatening interpretation of ambiguous stimuli (31, 32) is consistent with the high prevalence of panic attacks and panic disorder in COPD. In this disease, dyspnea is a frequent, potentially aversive symptom of an ultimately terminal illness. According to the cognitive model, individuals with COPD who interpret their dyspnea in a more extreme way, overestimating the imminent threat it presents, would be vulnerable to experiencing panic attacks and to developing panic disorder. As expected from this model, in the current study patients with COPD with panic attacks or disorder showed heightened sensitivity to loaded breathing, with consistently higher ratings than other subjects of their level of dyspnea.

This finding may be significant for the management of COPD- related anxiety. The positive treatment implication of the cognitive model, as noted by Smoller and Otto (33), is that, even in the absence of any improvement in pulmonary function, panic disorder in COPD may be helped by cognitive behavior therapy. This therapy is of proven efficacy for treating panic disorder in the absence of lung disease (34-36), but there is as yet only preliminary evidence for its usefulness for treating anxiety in COPD (37-41). The need for such intervention is supported by studies indicating that dyspnea and disability in COPD are worsened by the presence of anxiety and depression, independent of pulmonary function (42-46). Better recognition and treatment of comorbid psychological disorders in patients with COPD may also lead to significant cost savings for health services. Consistent with our results, a recent review found that anxiety and depression in patients with COPD and seven other chronic medical illnesses led to heightened physical symptom awareness (47). This increased awareness was associated with increased reporting of medical symptoms, use of medical services, and up to a doubling of medical costs (47). Panic disorder in the absence of respiratory disease is associated with avoidance of triggers for anxiety and with reassurance-seeking behavior (29, 30, 36). Increased perception of breathing difficulty in anxious patients with COPD may lead to underuse of physical exercise training and to excessive use of bronchodilators and of medical services.

The current study was designed with close attention to methodology, but there are some limitations to be considered. First, although these findings provide evidence of a relationship between anxiety, depression, and perceived dyspnea, the direction of causality has not been established, and it seems likely that there may be a reciprocal interaction. Second, whereas the presence of panic attacks and panic disorder was diagnosed with the ADIS-IV, our only measure of depressive symptoms was the HADS depression scale. In retrospect, it would have been useful to have also administered the ADIS-IV Mood Disorders section to the study sample. Also, in the interests of direct comparison of the results of this study with those of Hudgel and colleagues (16, 17) and Tiller and colleagues (18), it may have been of interest to ask subjects to directly rate the size of resistive loads in addition to the breathing difficulty the loads caused. However, we have no evidence that COPD panic patients had impaired perception of the relative magnitude of the loads. Future studies could include the formal diagnosis of mood disorders, and extend the current findings to larger samples. In such studies, asking subjects to separately rate the sensory and affective components of dyspnea during resistive loading, and to rate the size and perceived onset of the loads, may provide further useful information (14, 15, 48-50).

In conclusion, we found in this study that the presence of panic attacks or panic disorder in COPD was associated with heightened sensitivity to increasing inspiratory resistive loads, a finding that reinforces the importance of taking into account the influence of psychological factors on symptom perception in COPD.

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Acknowledgment : The authors acknowledge the assistance of staff in the Department of Respiratory Medicine at the Prince of Wales Hospital, Sydney, Australia, with the administration of this study, and of Dr. Sally Ramke with data collection.

AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject

Panic attacks are common in chronic obstructive pulmonary disease, and worsen disability, but the nature of their influence on respiratory symptoms has been uncertain.

What This Study Adds to the Field

The results of this study, using inspiratory resistive loading, provide evidence that panic attacks are associated with heightened sensitivity to inspiratory loads.

1Department of Liaison Psychiatry, Prince of Wales Hospital, and School of Psychology, University of Sydney, Sydney, Australia; 2Prince of Wales Medical Research Institute, University of New South Wales, Sydney, Australia; 3Department of Psychology, University of Sydney, Sydney, Australia; and 4Department of Respiratory Medicine, Prince of Wales Hospital, and Faculty of Medicine, University of New South Wales, Sydney, Australia

(Received in original form November 19, 2007; accepted in final form April 11, 2008)

Supported in part by an equipment grant from the Ramaciotti Foundation.